Hypertension incidence rises sharply after menopause, implicating a beneficial effect of estrogen on blood pressure (BP) regulation. However, there still are large gaps in the understanding of the underlying mechanisms and treatment of postmenopausal hypertension. Using intraneural microelectrodes to record postganglionic SNA in normotensive postmenopausal women, the applicant recently provided direct evidence for a major sympathoinhibitory effect of estrogen. Chronic estrogen replacement decreased SNA by 30% and caused a small decrease in 24-hour ambulatory BP. The most fascinating aspect of the work is that these effects were much more robust with transdermal than oral estrogen. She now wants to investigate: 1) the clinical importance of her findings by studying postmenopausal hypertension; and 2) underlying mechanism causing a greater effect of transdermal than oral estrogen on SNA and BP. She hypothesizes that the mechanism involves first-pass hepatic metabolism of oral estrogen leading to decreased hepatic production of insulin-like growth factor and excessive deposition of fat in the liver and around the abdominal viscera, factors which are likely to stimulate SNA and negate a primary sympathoinhibitory action of estrogen. To test her mechanistic hypothesis, she will need to acquire new research skills including euglycemic clamps and nuclear magnetic resonance measurements of regional fat distribution. She will use these techniques in exploring other clinical factors, such as concomitant administration of androgenic progestins, that are likely to engage some of the same adverse metabolic mechanisms and negate the antihypertensive effect of estrogen replacement. Finally, the applicant will learn to perform complementary experiments in a conscious rat model to determine the extent to which decreased activity of the sympathetic nervous system causes the antihypertensive effect of estrogen. The long-term goal of her work would be the discovery the most effective estrogen preparation that can prevent or treat hypertension in women after menopause.